COPD is a major health problem worldwide, but our level of understanding of its mechanisms, when compared to the other important airway disease, asthma, is relatively poor. COPD is a disease which progresses at a slow rate, which makes it very difficult to study its natural history and the impact of any therapeutic intervention. For all these reasons, it is vitally important to discover biomarkers that are elective for COPD, i.e., they are not general markers of lung inflammation and remodeling, and are prognostic for the rate of clinical deterioration. A number of non-invasive markers have been studied to date; to our knowledge, none of these have fulfilled the above criteria. As with other inflammatory lung diseases, a host of inflammatory and remodeling processes are involved in the pathogenesis of COPD, which render a singlemarker approach unlikely to succeed. We hypothesize that a number of proteins or protein isoforms are differentially expressed in the airway lining fluid in COPD and that these reflect the chronic pathology of COPD, rather than the chronic and acute effects of smoking. We propose to test this hypothesis using a proteomics approach as our primary, unbiased filter, to identify a set of 15 differentially expressed proteins (DEPs) that are present in a group of meticulously characterized subjects with COPD, but not present in those who have no evidence of lung damage despite an equivalent smoking history. Our programme is staged in a way to optimize the use of the state-of-the-art proteomics technology and precious archival samples collected over up to 17 years at the University of Nebraska and more recently in Southampton. Because we believe that patterns (groups) of biomarkers are more strongly related to COPD, we will apply multivariate analyses to identify the DEPs, which will thus become Early Candidate COPD-Selective Biomarkers. We will then develop antibodies against these in order to provide reagents for immunoassays. The latter will be applied to potentially as many as 480 subjects who have COPD, chronic severe asthma, or are healthy smokers or non-smokers. This will allow us to follow a logical sequence of further selection of biomarkers with respect to their selectivity for COPD, presence in early stages of smoke-induced lung damage and their prognostic value in terms of clinical deterioration and decline in lung function. Finally, applying the antibodies to archival lung tissue samples we will be able to localize the COPD-selective proteins to the airway and alveoli, adding valuable knowledge to our understanding of COPD mechanisms.